Bioinspired total synthesis of agelastatin A

Article abstract of DOI:10.1002/anie.201200959

A one-two punch: Two potentially biosynthetically relevant cyclizations of a keramadine analogue give agelastatin A (see scheme). A diastereoselective C-ring formation, which proceeds through a 5-exo-trig cyclization or a Nazarov cyclization of a red-colored N-acyliminium intermediate, generates the three contiguous stereocenters of the cyclopentane core. A silica gel assisted cyclization of a nagelamide J analogue gives agelastatin A. Copyright

Full text of DOI:10.1002/anie.201200959

Angewandte
Chemie
DOI: 10.1002/anie.201200959
Natural Product Synthesis
Bioinspired Total Synthesis of Agelastatin A**
Jeremy Chris P. Reyes and Daniel Romo*
Agelastatin A (1) is a unique tetracyclic member of the
growing family of pyrrole-2-aminoimidazole alkaloids
(PAIs).[1] This marine alkaloid was first isolated by Pietra
and co-workers in 1993 from the axinellid sponge Agelas
dendromorpha and was contaminated with a small amount of
a dibromo analogue, agelastatin B (2; Scheme 1).[2] In 1998,
two other congeners, agelastatins C (3) and D (4), were
isolated from the West Australian axinellid sponge Cymbas-
tela sp. by Molinski and co-workers.[3] More recently, Al-
Mourabit and co-workers isolated two additional members,
agelastatins E (5) and F (6), from Agelas dendromopha.[4] The
intriguing biogenesis of these alkaloids, which can be traced
back to simple precursors, such as oroidin and clathrodin, has
inspired several biosynthetic proposals but culminated in only
one purely bioinspired and elegant total synthesis, which was
recently described by Movassaghi et al.[5] The fact that there
has only been one bioinspired total synthesis is surprising
given that there are numerous total syntheses reported to
date[5,6] spurred by its challenging structure and it being
arguably the most bioactive member of the PAI family.
Agelastatin A (1) was found to be highly cytotoxic to a panel
of human-cancer cell lines (IC50ꢀs 97–703 nm),[7,8] potent in
inhibiting osteopontin (OPN)-mediated neoplastic transfor-
mation and metastasis,[9] and potentially antiangiogenic,[7]
antidiabetic,[10] and insecticidal.[3] The C ring, which contains
all four stereogenic centers found in the molecule, is clearly
the most challenging aspect of this molecule. In fact, most
previous synthetic strategies focused on building the func-
tionalized cyclopentane followed by late-stage construction of
the B and D rings. As part of our efforts to investigate the
biogenesis of PAIs,[11] we now report a concise bioinspired
approach to agelastatin A that is premised on the isolation of
the structurally related natural product, nagelamide J (8).
Two distinct and plausible biosynthetic presursors of
agelastatin A that have been isolated to date are cyclooroidin
(7)[12] and nagelamide J (8)[13] (Scheme 1). These natural
products each support a different order of B-ring and C-ring
formation in the biosynthesis of 1. Although the absolute
configuration of 8 is unknown, it is worth noting that the
configuration of the C7 stereocenter in 7 is opposite to that of
the corresponding center of agelastatin A. Movassaghi et al.
recently described a strategy that was premised on the
formation of an ent-cyclooroidin-like compound followed by
C-ring cyclization to deliver (ꢀ)-agelastatin A.[5] In contrast,
the synthetic strategy described herein highlights an alter-
native biogenetic pathway inspired by the nagelamide J
structural motif, which supports a biogenetic sequence
involving initial C-ring formation followed by B-ring forma-
tion.
Scheme 1. The agelastatins and structurally related PAIs.
Our bioinspired approach to agelastatin Awas also guided
by our previous experience with the ambivalent reactivity of
the imidazolone moiety in our studies toward dimeric PAIs.[14]
This reactivity is in stark contrast to what is commonly
invoked for the biogenesis of these targets, wherein an
oxidized imidazolone or aminoimidazole serves as an electro-
phile in subsequent cyclizations.[2a,15] These previous results
led us to consider a different biosynthetic pathway, which
proceeds through an N-acyliminium intermediate 13 that
could lead to sequential C- and B-ring formation through
a cascade process (Scheme 2). To this end, strategic discon-
[*] J. C. P. Reyes, Prof. Dr. D. Romo
Department of Chemistry, Texas A&M University
College Station, TX 77842-3012 (USA)
E-mail: romo@mail.chem.tamu.edu
Homepage: http://www.chem.tamu.edu/rgroup/romo
[**] We thank the NIH (GM52964) and the Welch Foundation (A-1280)
for generous support. We thank Luke Watson (NSF-REU student,
CHE-0755207) for technical assistance, Dr. Lisa M. Perez and Larisa
Mae Q. Reyes for helpful discussions regarding TD-DFT calcula-
tions, and Dr. Bhuvanesh Nattamai (TAMU) for obtaining the X-ray
structure of 10. We acknowledge the Laboratory for Molecular
Simulation (TAMU) and the Texas A&M Supercomputing Facility for
providing computing resources.
ꢀ
ꢀ
nections at the C4 C8 and C7 N12 bonds revealed carbino-
lamide 10; this intermediate is an oxidized version of
keramadine (9),[16] which is another isolated natural product
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200959.
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C-ring formation, could then be trapped by the adjacent
pyrrole nitrogen atom to form the B ring. Following an acid-
catalyzed hydration, this concise sequence would deliver
agelastatin A.
To access the N-acyliminium precursor 10, the imidazo-
lone alkynyl acetal 11 and N-methoxy pyrrole amide 12[6j]
were ultimately identified as suitable coupling partners. The
synthesis of imidazolone alkynyl acetal 11 commenced with
known imidazolone acid 18,[18] which is readily prepared from
tartaric acid 16 and N-methyl urea 17 in one step (Scheme 3).
Conversion of acid 18 into aldehyde 19 was accomplished in
a three-step sequence involving a single-pot esterification and
protection, reduction with DIBAl-H, and oxidation with
MnO2. The subjection of 19 to modified Seyferth–Gilbert
conditions by using the Ohira–Bestmann reagent 20[19] and
sodium methoxide[20] in a 1:1 mixture of methanol and
dichloromethane as solvent gave the desired alkyne. A
subsequent ZnII-mediated acetalization[21] furnished the tar-
geted imidazolone alkynyl acetal 11; this entire five-step
sequence could be readily performed on multigram scale.
The key coupling of acetal 11 and known N-methoxy
amido pyrrole 12[5j] was achieved by activation with SnCl4,[22]
thus providing ethoxy carbinolamide 21 (Scheme 3). A
substoichiometric amount (0.25 equivalents) of SnCl4 and
a 3 hour reaction time provided the best results in terms of
avoiding further decomposition and enabling optimal recov-
ery of both alkynyl acetal 11 and amido pyrrole 12. The
a effect associated with the N-methoxy group of the amide of
12 was critical for successful coupling because it engenders an
amide nitrogen atom of higher nucleophilicity than the
pyrrole nitrogen atom, thus enabling a chemoselective addi-
tion reaction.
Scheme 2. Bioinspired retrosynthetic analysis of agelastatin A and
proposed cascade process involving two cyclizations and proceeding
via two N-acyliminium intermediates 13 and 15.
that lends further credence to the biosynthetic proposal.
Keramadine 9, which was also isolated from an Agelas
sponge, is the only isolated monomeric PAI known to possess
a stable Z-configured olefin and notably bears the requisite
N1-methyl group found in the agelastatins. We envisioned
that a key N-acyliminium intermediate 13 could be derived
ꢀ
from 10 by using a Brønsted or Lewis acid. The C6 C7
Z olefin was introduced to exert conformational bias and
ꢀ
assist in the formation of the C4 C8 bond through a 5-exo-trig
cyclization or via pentadienyl cation 14, which is amenable to
a Nazarov 4p electrocyclization.[17] The second N-acylimi-
nium intermediate 15, which is generated as a consequence of
Reductive cleavage of the N-methoxy group was accom-
[23]
plished using SmI2 and following the designed late stage
Scheme 3. Bioinspired total synthesis of agelastatin A and 4,5-bis-epi-agelastatin A. In the crystal structure of 10, hydrogen atoms have been
removed for clarity and thermal ellipsoids are shown at 50% probability. DIBAl-H=diisobutylaluminium hydride, DMF=N,N-dimethylformamide,
KHMDS=potassium hexamethyldisilazide, Ms=methanesulfonyl, TFA=trifluoroacetic acid, THF=tetrahydrofuran, Tse=p-toluenesulfonylethyl.
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Lindlar reduction,[24] the desired cyclization precursor 10 was
obtained. X-ray crystallographic analysis[25] of this intermedi-
ate confirmed that the coupling step involved the addition of
the amide nitrogen atom (11!21) and not the pyrrole
nitrogen atom. When the Z olefin 10 was subjected to
a variety of Lewis and Brønsted acids, a deep-red solution
was formed immediately; upon addition of water, nucleo-
philic attack occurred regioselectively at C5, thus delivering
carbinolamine 24 a single diastereomer. When the deep-red
solution was treated with EtOH, the corresponding ethoxy
carbinolamine was formed (not shown). Formation of the
C ring was quite facile because complete conversion occurred
within 5 minutes; this ring formation also delivered three
contiguous stereocenters with the relative configuration
corresponding to the agelastatins and nagelamide J. Mecha-
nistically, this process occurs either through a 5-exo-trig
cyclization involving nucleophilic addition of the imidazolone
moiety to the N-acyliminium moiety of 13 or through
a Nazarov 4p electrocyclization of pentadienyl cation 14,
which is an alternative resonance form of 13, involving the
pseudoaromatic imidazolone.[17] However, the second cycli-
zation, which was envisioned to complete the synthesis and
involves nucleophilic addition of the pyrrole nitrogen atom to
C7 of the a,b-unsaturated N-acyliminium 23, did not proceed
under a variety of reaction conditions, including prolonged
reaction times, addition of non-nucleophilic bases, or expo-
sure to elevated temperatures. Under most reaction condi-
tions, the dark-red intermediate, which is presumably the acyl
iminium 23, was easily regenerated from 24 with both Lewis
and Brønsted acids. This intermediate persisted until a nucle-
ophile, for example water or methanol, was added; in the case
of water being the nucleophile, carbinolamine 24 was
reisolated. Conformational analysis of intermediate 23 sug-
recyclization. Attempted cyclizations with alternative sub-
strates revealed that the absence of the Tse group and the
presence of both the unprotected OH group at C5 and the
bromine substituent at C13 of the pyrrole ring of 25 were
essential for successful cyclization.
We were intrigued by the observed intense red color
during the first cyclization event (10!24); this color change
occurs immediately upon addition of acid even at low
temperature. Given the absorption of light in the visible
region, we suspected that the color may be due to a charge-
transfer complex involving the N-acyliminium intermediate
23. We used time-dependent density functional theory
(TD-DFT) calculations incorporating B3LYP and X3LYP
hybrid functionals to analyze excited states of this charged
intermediate and simpler substructures.[29] We compared
these values with those extracted from experimental UV/
Vis spectra of this colored intermediate and related simpler
substructures. These studies revealed that the red color of
intermediate 23, is likely due to a p!p* transition between
the HOMO, which is composed mostly of orbital contribu-
tions from the bromopyrrole amide moiety, and the LUMO,
which is composed mostly of orbital contributions from the
N-acyliminium moiety (Figure 1).
In summary, we accomplished a concise total synthesis of
agelastatin A (1) through two sequential, potentially biomim-
etic, cyclizations. The described sequential assembly of the C
and B rings provides evidence for the proposed reactivity of
a linear alkenyl imidazolone pyrrole, which leads to the
agelastatins; the strategy complements other approaches to
agelastatin that involve initial B-ring followed by C-ring
formation.[5] C-ring formation, which sets three contiguous
centers in a highly diastereoselective fashion, led to a reaction
mixture with an intense red color, which we propose
originates from a p!p* transition between the HOMO and
LUMO of N-acyliminium intermediate 23, a hypothesis,
which is supported by TD-DFT calculations. The final B-ring
ꢀ
gests that the C6 C7 olefin is out of plane with respect to the
N-acyliminium moiety by approximately 258, thus resulting in
a low degree of conjugation, which in turn is responsible for
the low electrophilicity at C7.[26] This analysis may also
explain why intermolecular addition of nucleophiles occurs
exclusively at the more electrophilic C5 carbon atom. More-
over, DFT calculations predict that products arising from
nucleophilic trapping at C7 were energetically disfavored by
approximately 2 kcalmolꢀ1 relative to those obtained upon
trapping at C5.[27]
An alternative strategy to form the final B ring from
bicyclic intermediate 24, would be a transient base-induced
opening of the cyclic urea (D ring) to a cyclopentenone
followed by an aza-Michael addition and reformation of the
cyclic urea. Interestingly, several previous syntheses of
agelastatin A that required late-stage B-ring closure
involved an enone intermediate, thus bolstering this idea
further.[6a,h,i,k,o,q] The Tse protecting group on one of the urea
nitrogen atoms was removed to enable greater conforma-
tional mobility and thus facilitate D-ring cleavage. After
much experimentation, we serendipitously found that bicyclic
intermediate 25 is readily converted into agelastatin A on
silica gel[28] under solvent-free conditions with mild heating.
4,5-Bis-epi-agelastatin A (26) was observed as a byproduct of
the cyclization and presumably arises from a retro-Nazarov
reaction or a retro-5-exo-trig ring opening followed by
Figure 1. Calculated HOMO and LUMO of the red-colored N-acylimi-
nium 23 and the p!p* transition, which based on TD-DFT calcula-
tions is proposed to be responsible for this color. Isovalue for
surface=0.04.
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closure was uniquely successful under solvent-free conditions
on silica gel with mild heating. The reaction sequence leading
from an oxidized keramadine analogue 10 via a nagelamide J
like intermediate 25 to agelastatin A is a provocative proposal
for the biosynthesis of the agelastatins and inspired the
concise route to the natural product reported herein. Further
studies of the described strategy, including development of an
enantioselective version,[30] are currently underway.
Received: February 3, 2012
Revised: May 1, 2012
Published online: && &&, &&&&
Keywords: alkaloids · biomimetic synthesis · N-acyliminium ·
.
Nazarov cyclization · pyrrole-2-amino imidazole alkaloids
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[29] See the Supporting Information for computational details and
both experimental and calculated UV/Vis spectra for intermedi-
ate 23 and related substructures.
[30] In preliminary studies, the use of 1.1 equiv of (R)-TRIP, (R)-3,3’-
bis(2,4,6-triisopropylphenyl)-1,1’-binaphthyl-2,2’-diyl hydrogen-
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7427; T. Akiyama, Patent U.S. 0276329 A1, Dec 7, 2006) to
promote the Nazarov-type cyclization of vinylimidazolone 10
gave carbinolamine 24 and then, following deprotection of the
Tse group, bicyclic adduct 25 in 63% ee. See the Supporting
Information for further details.
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Communications
Natural Product Synthesis
J. C. P. Reyes, D. Romo*
&&&& — &&&&
Bioinspired Total Synthesis of
Agelastatin A
A one-two punch: Two potentially bio-
synthetically relevant cyclizations of
a keramadine analogue give agelastatin A
(see scheme). A diastereoselective C-ring
formation, which proceeds through a 5-
exo-trig cyclization or a Nazarov cycliza-
tion of a red-colored N-acyliminium
intermediate, generates the three contig-
uous stereocenters of the cyclopentane
core. A silica gel assisted cyclization of
a nagelamide J analogue gives agelasta-
tin A.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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